Download Topic: Hereditary breast/ovarian cancer

 Topic: Hereditary breast/ovarian cancer
 Summary: Breast cancer is more common in older women but 1 in every 250 women in their 30s
could develop breast cancer over the next 10 years. The causes are not yet known, although a diet high in
fat, excess alcohol use and smoking are contributing factors. Women who carry the BRCA1 and BRCA2
gene mutations are at much higher risk of developing the disease.
 Bottom line: Increasing age is still the main risk factor for breast cancer but 5% to 10% of breast
cancer is due to an inherited BRCA1 or BRCA2 mutation. People with “high risk” family histories of
breast or ovarian cancer should be offered referral to genetics services, with a discussion of the benefits,
harms and limitations of genetic testing. Risk reduction mastectomy and salpingo-oophorectomy can
reduce mortality from breast and ovarian cancers in BRCA1 and BRCA2 carriers. Women with “low
risk” family histories should be reassured and offered screening as per general population guidelines.

 The Disease
 Approximately 80% of breast cancer occurs sporadically and 20% is inherited. About 5-10% is
hereditary (due to a single gene mutation) and 10-15% is familial (when a combination of genetic and
environmental risk factors are shared in a family). Genetic testing is available for hereditary breast and
ovarian cancer. About two-thirds of hereditary breast and ovarian cancer is related to mutations in the
BRCA1 and BRCA2 genes, which are germline mutations. The consequences of having a BRCA mutation
are outlined in Table 1.
 The BRCA Genes
 More than 2600 mutations have been found in the BRCA1 gene (located on chromosome 17) and the
BRCA2 gene (located on chromosome 13)
 The mutations have the following characteristics:
o Autosomal dominant transmission
o A carrier frequency of approximately 1/800 in the general (White) population and
1 per 40 to 50 people in the Ashkenazi Jewish population
o Both genes are tumor suppressors.
o Mutation leads to the following:
o an inability to regulate cell death
o uncontrolled growth leading to cancer
Consequences of having a faulty gene/ BRCA mutation (Table 1)
Estimated Risk in BRCA
Mutation Carriers
(by Age 70)
In General Population
Breast Cancer (in women)
50 - 85%
11%
Ovarian Cancer (BRCA1)
40 - 60%
1.5%
Ovarian Cancer (BRCA2)
10 - 20%
1.5%
Breast Cancer (in men)
up to 6%
Rare
 Who should be considered for testing?
 Referral for genetic counseling or testing should be offered to patients who meet the following criteria:
- Multiple cases of breast and/or ovarian cancer in family, especially
o in closely related relatives
o in more than one generation, and
o when breast cancer is diagnosed before age 50
- A family member with breast cancer diagnosed before age 35;
- A family member with both breast and ovarian cancers;
- A person with Ashkenazi Jewish heritage with a personal or family history of breast or ovarian cancer;
- A family member with primary cancer in both breasts if one or both cancers diagnosed before age 50;
- A family member with ovarian cancer;
- A family member with male breast cancer; or
- A family member with an identified BRCA1 or BRCA2 mutation.
Testing for the faulty genes, BRCA1 and BRCA2, involves a blood test, which is usually available at regional
genetic centres and some cancer centres. The test is covered by most provincial health plans if there is
substantial risk. In Ontario, for example, testing eligibility reflects a 10% or higher risk of mutation; affected
individuals in a family who are at highest risk are tested first. Genetic testing is generally offered to affected
individuals, where possible, unless a mutation has already been identified in the family. 1
 Benefits of genetic testing


Positive test result
- Clinical intervention can improve outcomes: risk reduction mastectomy reduces risk of breast cancer;
salpingo-oophorectomy reduces risk of ovarian and breast (if done premenopausally) cancer; and
magnetic resonance imaging enhances surveillance for breast cancer 2,3
- Family members at risk can be offered testing and identified.
- Positive health behaviours can be reinforced.
Negative test result
- Gives reassurance to individuals and their children.
 Harms/limitations of testing

There are potential negative aspects to genetic testing for mutations in the BRCA1 and BRCA2 genes:
Positive test result
- Adverse psychological reaction leading to family issues and distress
- Job or insurance discrimination
- Confidentiality issues, especially among family members
- Incomplete penetrance – having the mutation does not necessarily mean the patient will get the
disease
Negative test result
- Adverse psychological reaction, which can include survivor guilt
- Might lead to a complacent attitude to health
There are also cases of uninformative test results (when no mutations are detected, hereditary cancer
cannot be ruled out entirely) and unclear results (when variants of unknown significance are detected in
BRCA1 or BRCA2).
Web Resources: www.genetests.org
Review Articles:
1. Predictive Cancer Genetics Steering Committee. Ontario physicians’ guide to referral of patients with family
history of cancer to a familial cancer genetics clinic. Toronto, ON: Ontario Medical Association; 2001. Available
at: www.oma.org/pcomm/OMR/nov/01genetics.htm
2. Horsman D, Wilson BJ, Avard D, et al, on behalf of the National Hereditary Cancer Task Force. Clinical
Management Recommendations for Surveillance and Risk-Reduction Strategies for Hereditary Breast and Ovarian
Cancer Among Individuals Carrying a Deleterious BRCA1 or BRCA2 Mutation. J Obstet Gynaecol Can
2007;29(1):45–60.
3. Narod SA, Offit K. Prevention and management of hereditary breast cancer. J Clin Oncol. 2005; 23:1656-1663.
For a listing of genetics clinics in Canada, along with their respective contact and referral information, visit the
Canadian Association of Genetic Counsellors website at www.cagc-accg.ca.
“Gene Messenger” is for educational purposes only and should not be used as a substitute for clinical judgement. The “GenetiKit” team aims to ai d the practicing
clinician by providing informed opinions regarding genetic services that have been developed in a rigorous and evi dence-based manner. Physicians must use their
own clinical judgment in addition to published articles and the information presented herein. The members of the GenetiKit r esearch team assume no responsibility
or liability resulting from the use of information contained on “Gene Messenger.”
Updated November 2010
Funding provided by CIHR
Dr Carroll is Principal Investigator of the GenetiKit Project and is the Sydney G Frankfort Chair in Family Medicine at
Mount Sinai Hospital and an Associate Professor in the Department of Family Medicine at the University of Toronto.
In alphabetical order, other members of the GenetiKit Team are as follows: Dr Allanson is Chief of the Department of
Genetics at the Children's Hospital of Eastern Ontario (CHEO) in Ottawa, Ontario and Full Professor in the Department
of Pediatrics at the University of Ottawa. Dr Blaine is an Assistant Professor in the Department of Family and
Community Medicine at the University of Toronto in Ontario and Lead Physician of the STAR Family Health Team in
Stratford, Ontario. Ms Cremin is a Clinical Assistant Professor in the Department of Medical Genetics, University of
British Columbia. Ms Dorman is a Genetic Counselor at the Sudbury Regional Hospital in Ontario. Ms Gibbons is a
Genetic Counselor at the North York General Hospital in Ontario. Dr Graham is Vice-President of Knowledge
Translation, Canadian Institutes of Health Research.
Dr Grimshaw is a Professor in the Department of Medicine and Director of the Clinical Epidemiology Program at the
Ottawa Health Research Institute. Ms Honeywell is an Assistant Professor in the Department of Pediatrics at the
University of Ottawa and in the CHEO Departments of Genetics and Cardiology. Dr Meschino is a Clinical Geneticist at
North York General Hospital and Assistant Professor in the Department of Paediatrics at the University of Toronto. Ms
Permaul is a Research Associate in the Granovsky Gluskin Family Medicine Centre at Mount Sinai Hospital. Dr Wilson
is an Associate Professor in the Department of Epidemiology and Community Medicine at the University of Ottawa.